bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2021‒08‒08
twenty papers selected by
Oltea Sampetrean
Keio University

  1. Cancers (Basel). 2021 Jul 22. pii: 3686. [Epub ahead of print]13(15):
      Glioblastoma (GBM) accounts for more than 50% of all primary malignancies of the brain. Current standard treatment regimen for GBM includes maximal surgical resection followed by radiation and adjuvant chemotherapy. However, due to the heterogeneity of the tumor cells, tumor recurrence is often inevitable. The prognosis of patients with glioma is, thus, dismal. Glioma is a highly angiogenic tumor yet immunologically cold. As such, evolving studies have focused on designing strategies that specifically target the tyrosine kinase receptors of angiokines and encourage immune infiltration. Recent promising results from immunotherapies on other cancer types have prompted further investigations of this therapy in GBM. In this article, we reviewed the pathological angiogenesis and immune reactivity in glioma, as well as its target for drug development, and we discussed future directions in glioma therapy.
    Keywords:  angiogenesis; glioblastoma; immune checkpoint blockade; immune microenvironment
  2. Br J Cancer. 2021 Aug 04.
      The prognosis for patients with glioblastoma (GBM), the most common and malignant type of primary brain tumour, is very poor, despite current standard treatments such as surgery, radiotherapy and chemotherapy. Moreover, the immunosuppressive tumour microenvironment hinders the development of effective immunotherapies for GBM. Cytokines such as interleukin-10 (IL-10) play a major role in modulating the activity of infiltrating immune cells and tumour cells in GBM, predominantly conferring an immunosuppressive action; however, in some circumstances, IL-10 can have an immunostimulatory effect. Elucidating the function of IL-10 in GBM is necessary to better strategise and improve the efficacy of immunotherapy. This review discusses the immunostimulatory and immunosuppressive roles of IL-10 in the GBM tumour microenvironment while considering IL-10-targeted treatment strategies. The molecular mechanisms that underlie the expression of IL-10 in various cell types are also outlined, and how this resulting information might provide an avenue for the improvement of immunotherapy in GBM is explored.
  3. Cancers (Basel). 2021 Aug 02. pii: 3899. [Epub ahead of print]13(15):
      Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM-expansion depends on a dense vascular network and, coherently, GBMs are highly angiogenic. However, new intratumoral blood vessels are often aberrant with consequences for blood-flow and vascular barrier function. Hence, the delivery of chemotherapeutics into GBM can be compromised. Furthermore, leaky vessels support edema-formation, which can result in severe neurological deficits. The secreted signaling peptide Apelin (APLN) plays an important role in the formation of GBM blood vessels. Both APLN and the Apelin receptor (APLNR) are upregulated in GBM cells and control tumor cell invasiveness. Here we summarize the current evidence on the role of APLN/APLNR signaling during brain tumor pathology. We show that targeting APLN/APLNR can induce anti-angiogenic effects in GBM and simultaneously blunt GBM cell infiltration. In addition, we discuss how manipulation of APLN/APLNR signaling in GBM leads to the normalization of tumor vessels and thereby supports chemotherapy, reduces edema, and improves anti-tumorigenic immune reactions. Hence, therapeutic targeting of APLN/APLNR signaling offers an interesting option to address different pathological hallmarks of GBM.
    Keywords:  APLNR; Apelin (APLN); Glioblastoma (GBM); angiogenesis; invasion; pericytes; tumor associated myeloid cells (TAM); tumor microenvironment (TME); tumor parenchyma; vascular normalization
  4. Cancers (Basel). 2021 Jul 24. pii: 3721. [Epub ahead of print]13(15):
      Glioblastoma is the most frequent and the most aggressive brain tumor. It is notoriously resistant to current treatments, and the prognosis remains dismal. Immunotherapies have revolutionized the treatment of numerous cancer types and generate great hope for glioblastoma, alas without success until now. In this review, the rationale underlying immune targeting of glioblastoma, as well as the challenges faced when targeting these highly immunosuppressive tumors, are discussed. Innovative immune-targeting strategies including cancer vaccines, oncolytic viruses, checkpoint blockade inhibitors, adoptive cell transfer, and CAR T cells that have been investigated in glioblastoma are reviewed. From a clinical perspective, key clinical trial findings and ongoing trials are discussed for each approach. Finally, limitations, either biological or arising from trial designs are analyzed, and strategies to overcome them are presented. Proof of efficacy for immunotherapy approaches remains to be demonstrated in glioblastoma, but our rapidly expanding understanding of its biology, its immune microenvironment, and the emergence of novel promising combinatorial approaches might allow researchers to finally fulfill the medical need for GBM patients.
    Keywords:  CAR T cell; checkpoint inhibitor; glioblastoma; immunotherapy; oncolytic virus; vaccine
  5. Neuro Oncol. 2021 Aug 04. pii: noab182. [Epub ahead of print]
      BACKGROUND: Rigorous preclinical studies of chimeric antigen receptor (CAR) immunotherapy will require large quantities of consistent and high-quality CAR-transduced T (CART)-cells that can be used in syngeneic mouse glioblastoma (GBM) models. To this end, we developed a novel transgenic (Tg) mouse strain with a fully murinized CAR targeting epidermal growth factor receptor variant III (EGFRvIII).METHODS: We first established the murinized version of EGFRvIII-CAR and validated its function using a retroviral vector (RV) in C57BL/6J mice bearing syngeneic SB28 GBM expressing EGFRvIII. Next, we created C57BL/6J-background Tg mice carrying the anti-EGFRvIII-CAR downstream of a Lox-Stop-Lox cassette in the Rosa26 locus. We bred these mice with CD4-Cre Tg mice to allow CAR expression on T-cells and evaluated the function of the CART-cells both in vitro and in vivo. To inhibit immunosuppressive myeloid cells within SB28 GBM, we also evaluated a combination approach of CART and an anti-EP4 compound (ONO-AE3-208).
    RESULTS: Both RV- and Tg-CART-cells demonstrated specific cytotoxic activities against SB28-EGFRvIII cells. A single intravenous infusion of EGFRvIII-CART-cells prolonged the survival of glioma-bearing mice when preceded by a lymphodepletion regimen with recurrent tumors displaying profound EGFRvIII loss. The addition of ONO-AE3-208 resulted in long-term survival in a fraction of CART-treated mice and those survivors demonstrated delayed growth of subcutaneously re-challenged both EGFRvIII + and parental EGFRvIII - SB28.
    CONCLUSION: Our new syngeneic CAR Tg mouse model can serve as a useful tool to address clinically relevant questions and develop future immunotherapeutic strategies.
    Keywords:  CART-cells; EGFRvIII; glioblastoma; immunotherapy; transgenic
  6. Neuro Oncol. 2021 Aug 04. pii: noab181. [Epub ahead of print]
      BACKGROUND: Tumor vessels in glioma are molecularly and functionally abnormal, contributing to treatment resistance. Proteins differentially expressed in glioma vessels can change vessel phenotype and be targeted for therapy. ELTD1 (Adgrl4) is an orphan member of the adhesion G-protein-coupled receptor family upregulated in glioma vessels, and has been suggested as a potential therapeutic target. However, the role of ELTD1 in regulating vessel function in glioblastoma is poorly understood.METHODS: ELTD1 expression in human gliomas and its association with patient survival was determined using tissue microarrays and public databases. The role of ELTD1 in regulating tumor vessel phenotype was analyzed using orthotopic glioma models and ELTD1 -/- mice. Endothelial cells isolated from murine gliomas were transcriptionally profiled to determine differentially expressed genes and pathways. The consequence of ELTD1-deletion on glioma immunity was determined by treating tumor bearing mice with PD-1-blocking antibodies.
    RESULTS: ELTD1 levels were upregulated in human glioma vessels, increased with tumor malignancy, and were associated with poor patient survival. Progression of orthotopic gliomas was not affected by ELTD1-deletion, however, tumor vascular function was improved in ELTD1 -/- mice. Bioinformatic analysis of differentially expressed genes indicated increased inflammatory response and decreased proliferation in tumor endothelium in ELTD1 -/- mice. Consistent with an enhanced inflammatory response, ELTD1-deletion improved T-cell infiltration in GL261-bearing mice after PD-1 checkpoint blockade.
    CONCLUSION: Our data demonstrate that ELTD1 participates in inducing vascular dysfunction in glioma, and suggests that targeting of ELTD1 may normalize the vessels and improve the response to immunotherapy.
    Keywords:  ADGRL4; ELTD1; glioma; immunotherapy; vascular normalization
  7. Acta Neuropathol Commun. 2021 Aug 04. 9(1): 133
      The invasive behavior of glioblastoma, the most aggressive primary brain tumor, is considered highly relevant for tumor recurrence. However, the invasion zone is difficult to visualize by Magnetic Resonance Imaging (MRI) and is protected by the blood brain barrier, posing a particular challenge for treatment. We report biological features of invasive growth accompanying tumor progression and invasion based on associated metabolic and transcriptomic changes observed in patient derived orthotopic xenografts (PDOX) in the mouse and the corresponding patients' tumors. The evolution of metabolic changes, followed in vivo longitudinally by 1H Magnetic Resonance Spectroscopy (1H MRS) at ultra-high field, reflected growth and the invasive properties of the human glioblastoma transplanted into the brains of mice (PDOX). Comparison of MRS derived metabolite signatures, reflecting temporal changes of tumor development and invasion in PDOX, revealed high similarity to spatial metabolite signatures of combined multi-voxel MRS analyses sampled across different areas of the patients' tumors. Pathway analyses of the transcriptome associated with the metabolite profiles of the PDOX, identified molecular signatures of invasion, comprising extracellular matrix degradation and reorganization, growth factor binding, and vascular remodeling. Specific analysis of expression signatures from the invaded mouse brain, revealed extent of invasion dependent induction of immune response, recapitulating respective signatures observed in glioblastoma. Integrating metabolic profiles and gene expression of highly invasive PDOX provided insights into progression and invasion associated mechanisms of extracellular matrix remodeling that is essential for cell-cell communication and regulation of cellular processes. Structural changes and biochemical properties of the extracellular matrix are of importance for the biological behavior of tumors and may be druggable. Ultra-high field MRS reveals to be suitable for in vivo monitoring of progression in the non-enhancing infiltration zone of glioblastoma.
    Keywords:  1H MRS at ultra-high fields (UHF); Glioblastoma; Invasion; Patient-derived orthotopic xenografts (PDOX); Transcriptome; Tumor host interaction
  8. Sci Rep. 2021 Aug 02. 11(1): 15668
      Genome-wide studies have uncovered specific genetic alterations, transcriptomic patterns and epigenetic profiles associated with different glioma types. We have recently created a unique atlas encompassing genome-wide profiles of open chromatin, histone H3K27ac and H3Kme3 modifications, DNA methylation and transcriptomes of 33 glioma samples of different grades. Here, we intersected genome-wide atlas data with topologically associating domains (TADs) and demonstrated that the chromatin organization and epigenetic landscape of enhancers have a strong impact on genes differentially expressed in WHO low grade versus high grade gliomas. We identified TADs enriched in glioma grade-specific genes and/or epigenetic marks. We found the set of transcription factors, including REST, E2F1 and NFKB1, that are most likely to regulate gene expression in multiple TADs, containing specific glioma-related genes. Moreover, many genes associated with the cell-matrix adhesion Gene Ontology group, in particular 14 PROTOCADHERINs, were found to be regulated by long-range contacts with enhancers. Presented results demonstrate the existence of epigenetic differences associated with chromatin organization driving differential gene expression in gliomas of different malignancy.
  9. Cancers (Basel). 2021 Jul 26. pii: 3750. [Epub ahead of print]13(15):
      Management of glioblastoma is a clinical challenge since very few systemic treatments have shown clinical efficacy in recurrent disease. Thanks to an increased knowledge of the biological and molecular mechanisms related to disease progression and growth, promising novel treatment strategies are emerging. The expanding availability of innovative compounds requires the design of a new generation of clinical trials, testing experimental compounds in a short time and tailoring the sample cohort based on molecular and clinical behaviors. In this review, we focused our attention on the assessment of promising novel treatment approaches, discussing novel trial design and possible future fields of development in this setting.
    Keywords:  GBM; glioblastoma; new trial design; newly diagnosed glioblastoma; recurrent glioblastoma
  10. Cancers (Basel). 2021 Jul 27. pii: 3764. [Epub ahead of print]13(15):
      Background: Involvement of the subventricular zone (SVZ) in glioblastoma is associated with poor prognosis and is associated with specific tumor-biological characteristics. The SVZ microenvironment can influence gene expression in glioblastoma cells in preclinical models. We aimed to investigate whether the SVZ microenvironment has any influence on intratumoral gene expression patterns in glioblastoma patients. Methods: The publicly available Ivy Glioblastoma database contains clinical, radiological and whole exome sequencing data from multiple regions from resected glioblastomas. SVZ involvement of the various tissue samples was evaluated on MRI scans. In tumors that contacted the SVZ, we performed gene expression analyses and gene set enrichment analyses to compare gene (set) expression in tumor regions within the SVZ to tumor regions outside the SVZ. We also compared these samples to glioblastomas that did not contact the SVZ. Results: Within glioblastomas that contacted the SVZ, tissue samples within the SVZ showed enrichment of gene sets involved in (epithelial-)mesenchymal transition, NF-κB and STAT3 signaling, angiogenesis and hypoxia, compared to the samples outside of the SVZ region from the same tumors (p < 0.05, FDR < 0.25). Comparison of glioblastoma samples within the SVZ region to samples from tumors that did not contact the SVZ yielded similar results. In contrast, we observed no differences when comparing the samples outside of the SVZ from SVZ-contacting glioblastomas with samples from glioblastomas that did not contact the SVZ at all. Conclusion: Glioblastoma samples in the SVZ region are enriched for increased (epithelial-)mesenchymal transition and angiogenesis/hypoxia signaling, possibly mediated by the SVZ microenvironment.
    Keywords:  (epithelial-)mesenchymal transition; gene set enrichment analysis; glioblastoma; intratumoral heterogeneity; subventricular zone
  11. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00907-4. [Epub ahead of print]36(5): 109480
      Recent multi-omics studies show different immune tumor microenvironment (TME) compositions in glioblastoma (GBM). However, temporal comprehensive knowledge of the TME from initiation of the disease remains sparse. We use Cre recombinase (Cre)-inducible lentiviral murine GBM models to compare the cellular evolution of the immune TME in tumors initiated from different oncogenic drivers. We show that neutrophils infiltrate early during tumor progression primarily in the mesenchymal GBM model. Depleting neutrophils in vivo at the onset of disease accelerates tumor growth and reduces the median overall survival time of mice. We show that, as a tumor progresses, bone marrow-derived neutrophils are skewed toward a phenotype associated with pro-tumorigenic processes. Our findings suggest that GBM can remotely regulate systemic myeloid differentiation in the bone marrow to generate neutrophils pre-committed to a tumor-supportive phenotype. This work reveals plasticity in the systemic immune host microenvironment, suggesting an additional point of intervention in GBM treatment.
    Keywords:  cancer stem cells; glioblastoma; mouse models of cancer; neutrophils; plasticity; systemic reprogramming; tumor microenvironment
  12. Sci Rep. 2021 Aug 05. 11(1): 15908
      While specific microRNA (miRNA) signatures have been identified in glioblastoma (GBM), the intratumour heterogeneity in miRNA expression has not yet been characterised. In this study, we reveal significant alterations in miRNA expression across three GBM tumour regions: the core, rim, and invasive margin. Our miRNA profiling analysis showed that miR-330-5p and miR-215-5p were upregulated in the invasive margin relative to the core and the rim regions, while miR-619-5p, miR-4440 and miR-4793-3p were downregulated. Functional analysis of newly identified miRNAs suggests their involvement in regulating lipid metabolic pathways. Subsequent liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectroscopy (LC-MS/MS) profiling of the intracellular metabolome and the lipidome of GBM cells with dysregulated miRNA expression confirmed the alteration in the metabolite levels associated with lipid metabolism. The identification of regional miRNA expression signatures may underlie the metabolic heterogeneity within the GBM tumour and understanding this relationship may open new avenues for the GBM treatment.
  13. Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab077
      Background: Although microscopic assessment is still the diagnostic gold standard in pathology, non-light microscopic methods such as new imaging methods and molecular pathology have considerably contributed to more precise diagnostics. As an upcoming method, Raman spectroscopy (RS) offers a "molecular fingerprint" that could be used to differentiate tissue heterogeneity or diagnostic entities. RS has been successfully applied on fresh and frozen tissue, however more aggressively, chemically treated tissue such as formalin-fixed, paraffin-embedded (FFPE) samples are challenging for RS.Methods: To address this issue, we examined FFPE samples of morphologically highly heterogeneous glioblastoma (GBM) using RS in order to classify histologically defined GBM areas according to RS spectral properties. We have set up an SVM (support vector machine)-based classifier in a training cohort and corroborated our findings in a validation cohort.
    Results: Our trained classifier identified distinct histological areas such as tumor core and necroses in GBM with an overall accuracy of 70.5% based on the spectral properties of RS. With an absolute misclassification of 21 out of 471 Raman measurements, our classifier has the property of precisely distinguishing between normal-appearing brain tissue and necrosis. When verifying the suitability of our classifier system in a second independent dataset, very little overlap between necrosis and normal-appearing brain tissue can be detected.
    Conclusion: These findings show that histologically highly variable samples such as GBM can be reliably recognized by their spectral properties using RS. As conclusion, we propose that RS may serve useful as a future method in the pathological toolbox.
    Keywords:  FFPE; Raman spectroscopy; glioblastoma; machine learning; pathology
  14. Theranostics. 2021 ;11(16): 7911-7947
      Despite numerous clinical trials and pre-clinical developments, the treatment of glioblastoma (GB) remains a challenge. The current survival rate of GB averages one year, even with an optimal standard of care. However, the future promises efficient patient-tailored treatments, including targeted radionuclide therapy (TRT). Advances in radiopharmaceutical development have unlocked the possibility to assess disease at the molecular level allowing individual diagnosis. This leads to the possibility of choosing a tailored, targeted approach for therapeutic modalities. Therapeutic modalities based on radiopharmaceuticals are an exciting development with great potential to promote a personalised approach to medicine. However, an effective targeted radionuclide therapy (TRT) for the treatment of GB entails caveats and requisites. This review provides an overview of existing nuclear imaging and TRT strategies for GB. A critical discussion of the optimal characteristics for new GB targeting therapeutic radiopharmaceuticals and clinical indications are provided. Considerations for target selection are discussed, i.e. specific presence of the target, expression level and pharmacological access to the target, with particular attention to blood-brain barrier crossing. An overview of the most promising radionuclides is given along with a validation of the relevant radiopharmaceuticals and theranostic agents (based on small molecules, peptides and monoclonal antibodies). Moreover, toxicity issues and safety pharmacology aspects will be presented, both in general and for the brain in particular.
    Keywords:  PET SPECT imaging; glioblastoma; radiochemistry; targeted radionuclide therapy; theranostics
  15. Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab092
      Background: Glioblastoma remains incurable despite treatment with surgery, radiation therapy, and cytotoxic chemotherapy, prompting the search for a metabolic pathway unique to glioblastoma cells.13C MR spectroscopic imaging with hyperpolarized pyruvate can demonstrate alterations in pyruvate metabolism in these tumors.Methods: Three patients with diagnostic MRI suggestive of a glioblastoma were scanned at 3 T 1-2 days prior to tumor resection using a 13C/1H dual-frequency RF coil and a 13C/1H-integrated MR protocol, which consists of a series of 1H MR sequences (T2 FLAIR, arterial spin labeling and contrast-enhanced [CE] T1) and 13C spectroscopic imaging with hyperpolarized [1-13C]pyruvate. Dynamic spiral chemical shift imaging was used for 13C data acquisition. Surgical navigation was used to correlate the locations of tissue samples submitted for histology with the changes seen on the diagnostic MR scans and the 13C spectroscopic images.
    Results: Each tumor was histologically confirmed to be a WHO grade IV glioblastoma with isocitrate dehydrogenase wild type. Total hyperpolarized 13C signals detected near the tumor mass reflected altered tissue perfusion near the tumor. For each tumor, a hyperintense [1-13C]lactate signal was detected both within CE and T2-FLAIR regions on the 1H diagnostic images (P = .008). [13C]bicarbonate signal was maintained or decreased in the lesion but the observation was not significant (P = .3).
    Conclusions: Prior to surgical resection, 13C MR spectroscopic imaging with hyperpolarized pyruvate reveals increased lactate production in regions of histologically confirmed glioblastoma.
    Keywords:  bicarbonate; glioblastoma; hyperpolarized; preoperative; pyruvate
  16. Cancer Res. 2021 Jul 31. pii: canres.0985.2021. [Epub ahead of print]
      WHO grade II isocitrate dehydrogenase mutant gliomas (IDHmut-LGGs) grow slowly but frequently undergo malignant transformation, which eventually leads to premature death. Chemotherapy and radiotherapy treatments prolong survival, but can also induce genetic (or epigenetic) alterations involved in transformation. Here, we developed a mathematical model of tumor progression based on serial tumor volume data and treatment history of 276 IDHmut-LGGs classified by chromosome 1p/19q codeletion (IDHmut/1p19qcodel and IDHmut/1p19qnoncodel) and performed genome-wide mutational analyses, including targeted sequencing and longitudinal whole exome sequencing data. These analyses showed that tumor mutational burden correlated positively with malignant transformation rate, and chemotherapy and radiotherapy significantly suppressed tumor growth but increased malignant transformation rate per cell by 1.8-2.8 times compared to before treatment. This model revealed that prompt adjuvant chemoradiotherapy prolonged malignant transformation-free survival in small IDHmut-LGGs ({less than or equal to} 50 cm3). Furthermore, optimal treatment differed according to genetic alterations for large IDHmut-LGGs (> 50 cm3); adjuvant therapies delayed malignant transformation in IDHmut/1p19qnoncodel but often accelerated it in IDHmut/1p19qcodel. Notably, phosphoinositide 3-kinase mutation was not associated with malignant transformation but increased net postoperative proliferation rate and decreased malignant transformation-free survival, prompting the need for adjuvant therapy in IDHmut/1p19qcodel. Overall, this model uncovered therapeutic strategies that could prevent malignant transformation and, consequently, improve overall survival in patients with IDHmut-LGGs.
  17. Lancet Oncol. 2021 Aug;pii: S1470-2045(21)00378-8. [Epub ahead of print]22(8): e345
  18. Neuro Oncol. 2021 Aug 04. pii: noab188. [Epub ahead of print]
      BACKGROUND: A phase 1/2 trial of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase (HDAC) inhibitor, was conducted in children with newly-diagnosed diffuse intrinsic pontine glioma (DIPG) through the Children's Oncology Group (COG) to: 1) determine the recommended phase 2 dose (RP2D) of vorinostat given concurrently with radiation therapy; 2) document the toxicities of continuing vorinostat as maintenance therapy after radiation; and 3) to determine the efficacy of this regimen by comparing the risk of progression or death with an historical model from past COG trials.METHODS: Vorinostat was given once daily, Monday through Friday, during radiation therapy (54 Gy in 30 fractions), and then continued at 230 mg/m 2 daily for a maximum of twelve 28-day cycles.
    RESULTS: Twelve patients enrolled on the phase 1 study; the RP2D of vorinostat given concurrently with radiation was 230 mg/m 2/day, Monday through Friday weekly. The six patients enrolled at the RP2D and an additional 64 patients enrolled onto the phase 2 study contributed to the efficacy assessment. Although vorinostat was well-tolerated, did not interrupt radiation therapy, and was permanently discontinued in only 8.6% of patients due to toxicities, risk for EFS-event was not significantly reduced compared with the target risk derived from historical COG data (p = 0.32; 1-sided). The 1-year EFS was 5.85% (95% CI 1.89 - 13.1%) and 1-year OS was 39.2% (27.8 - 50.5%).
    CONCLUSIONS: Vorinostat given concurrently with radiation followed by vorinostat monotherapy was well tolerated in children with newly-diagnosed DIPG but failed to improve outcome.
    Keywords:  children; diffuse intrinsic pontine glioma; phase 1/2 clinical trials; suberoylanilide hydroxamic acid; vorinostat